Interleukin 1 (IL-1) receptor associated kinase (IRAK) functions as an intracellular signal transducer for the pro-inflammatory cytokine IL-1. IL-1 treatment of cells induces the complex formation of the two IL-1 receptor chains, IL-1R1 and IL-1RAcP, which recruits an adaptor molecule designated as MyD88 which binds to IRAK. IRAK is subsequently phosphorylated, released from the receptor complex to interact with TRAF6. TRAF6 triggers either the NIK/IKK kinase cascade to activate the transcription factor NF-.kappa.B or an undefined kinase cascade to activate the transcription factor AP-1. Both transcription factors regulate large numbers of genes that regulate immune and inflammatory responses.
The genome project has facilitated the identification of a large number of membrane bound receptor-like molecules that are related to IL-1RI and IL-1RAcP by sequence homology. One member of this family, IL-1RrP, has been recently shown to function as a receptor of an IL-1 related cytokine, IL-1 8, that regulates immune response by promoting the production of interferon.gamma.. Like IL-1RI and IL-1RAcP, IL-1RrP signals NF-.kappa.B activation. Gene disruption experiments and biochemical analyzes indicate that IL-1RrP also utilizes MyD88 and IRAK and TRAF6 as intracellular signal transducers.
Although MyD88 deficient mice failed to respond to IL-1 and IL-18, IRAK deficient mice still have a residual response to IL-1. This observation indicates that other molecules in the cells can partially substitute for the function of IRAK in IL-1 signaling. Recently, an IRAK-related molecule designated IRAK2, was described. Although upon over expression, IRAK2 could interact with IL-1R and IRAK, it has not been shown to be recruited to the receptor complex after IL-1 treatment like IRAK. Therefore, we searched for molecules that can substitute for IRAK in an IL-1 response.